COVID-19 updates

A retrospective analysis of 96,032 patients from the proprietary Surgisphere multinational database of information from electronic health records, supply chain databases, and financial records compared patients that received chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide to patients who received none of these treatments. The analysis found no benefit for chloroquine or hydroxychloroquine with or without a macrolide and the data suggested an increase in morbidity due to a higher incidence of arrhythmias. Due to the analysis of this trial, the WHO put a hold on the hydroxychloroquine arm of the trial for a safety review. The analysis was published in the journal Lancet. The Lancet editors issued an open letter to the authors of the analysis questioning the data integrity, highlighting flaws in the data aggregation and inadequate adjustment of confounders. They also pointed out the consequences of using a widely reported article on treatment decisions, clinical trials and public health policy. Information from the same database was used in an analysis of the safety of antihypertensive use in COVID-19 patients and published in the New England Journal of Medicine. The editors of NEJM published a similar letter of concern. After examining the concerns about the Lancet study, the WHO restarted the hydroxychloroquine arm of the study. Both NEJM and Lancet have asked to review the Surgisphere database and methods used to extract, store and retrieve data. In a response, Surgisphere has agreed to an independent academic audit to validate where the data comes from, the database, and the statistical analysis required for the two studies. Both the study published in Lancet and in NEJM have been retracted, because all authors of each article were not granted access to the full data set for either study.

In a 14-day, 821 patient trial, prophylactic use of hydroxychloroquine did not reduce the incidence of infection compared to placebo (11.8% vs 14.3%) in healthy patients exposed to a known or suspected COVID-19 patient. An NEJM editorial points out inconsistent proof of exposure and confirmation of the development of infection. The prophylaxis regimen was initialed three days or later after exposure, which could have also decreased efficacy.

COVID-19 Antibodies

In a 28-day, 103 patient Chinese trial, treatment with convalescent plasma did not lead to a statistical difference in clinical improvement (discharge or reduction in severity) compared to placebo (51.9% vs 43.1%) in patients with severe or critical COVID-19 infection. An editorial in JAMA pointed out that patients with severe COVID-19 demonstrated clinical improvement (91.3% vs 68.2%) but not patients with critical infection (20.7% vs 24.1%).

Operation Warp Speed, a U.S. program designed to rapidly accelerate the development and availability of a vaccine for COVID-19, has chosen five vaccines they consider having the best chance to succeed. The vaccines chosen are being developed by Moderna (currently in Phase II), AstraZeneca (currently Phase II), Pfizer (currently in two Phase I/II trials) and vaccines in pre-clinical development from Johnson & Johnson and Merck.

COVID-19 Resources

The FDA has created a resource page of COVID-19 information for health care professionals. The page will be continuously updated and include information on emergency use authorizations, personal protective equipment, and medical products, including investigational drugs and fraudulent devices.

Gilead announced that in the first 585 patients enrolled in an 11-day, Phase III trial (NCT04292730), patients treated with a 5-day course of remdesivir were 65% more likely to have at least a 1-point improvement on a seven-point scale that runs from death to not hospitalized in hospitalized patients with moderate COVID-19. A 10-day course of remdesivir did not differ from placebo in the treatment of moderate COVID-19 patients.

COVID-19 Antibodies

Lilly initiated a Phase I trial to evaluate a single dose of LY-CoV555 as a treatment for hospitalized COVID-19 patients at the beginning of June. Results are expected by the end of June and positive results will lead to a Phase II trial. LY-CoV555 is a neutralizing IgG1 monoclonal antibody targeting the spike protein of SARS-CoV-2. AbCellera and NIAID identified the antibody from a COVID-19 patient and Lilly developed a way to produce the antibody.

COVID-19 Vaccine

Moderna initiated a 600 patient, Phase II trial in late May. Patients will be given two doses 28-days apart of mRNA-1273 vaccine low dose (50 micrograms), high dose (100 micrograms) or placebo. Half of the patients enrolled in the trial will be older than 55. The Phase III trial is expected to begin in July 2020. Moderna hopes to file a BLA for mRNA-1273 in early 2021.

Results were published from the first 397 patients enrolled in the 6,000 patient, Phase III, SIMPLE trial (NCT04292899), which found no difference in efficacy, measured on a seven-point scale that runs from death to not hospitalized, between a 5-day course of remdesivir and a 10-day course in hospitalized patients with severe COVID-19. The data suggested that earlier treatment was more efficacious than later treatment. An accompanying editorial recommended that 5-day treatment be given priority due to the limited supply of the drug.

Roche and Gilead will compare the effect of tocilizumab plus remdesivir to placebo on clinical status, mortality, mechanical ventilation use and intensive care unit variables in the 60-day, 450 patient, Phase III REMDACTA trial in patients with severe COVID-19 pneumonia.

PB1046

PhaseBio is evaluating PB1046 as a treatment for hospitalized COVID-19 patients at risk for clinical deterioration and acute respiratory distress syndrome (ARDS) in the 210 patient, Phase II, VANGARD trial. The trial is expected to begin at the end of June with results from the trial expected by the end of 2020. PB1046 is an investigational vasoactive intestinal peptide (VPAC2) receptor-selective agonist being developed by PhaseBio as a treatment of pulmonary arterial hypertension.

In the 29-day, 1,059 patient, Phase III, Adaptive COVID-19 Treatment Trial (ACTT-1) trial (NCT04280705), where patients treated with remdesivir for up to ten days had a median time of recovery (hospital discharge or returning to normal activity level) of 11 days compared to 15 days with placebo in patients with severe COVID-19. There was a non-significant difference in the mortality rate of 8% with remdesivir compared to 11.6% with placebo.

Hydroxychloroquine and Chloroquine

​A retrospective analysis of 96,032 patients from a multinational COVID-19 infection registry compared patients that received chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide to patients who received none of these treatments. The analysis found no benefit for chloroquine or hydroxychloroquine with or without a macrolide and the data suggested an increase in morbidity due to a higher incidence of arrhythmias. Due to the results of this trial, the WHO has put a hold on the hydroxychloroquine arm of the trial for a safety review.

Convalescent Plasma

In an unreviewed, unedited report of a 195 patient trial, 39 patients that received a single transfusion of convalescent plasma required the same or less supplemental oxygen and non-intubated patients had a mortality benefit compared to a set of retrospectively selected matched controls in hospitalized patients with severe COVID-19.

COVID-19 Vaccines

BARDA has provided AstraZeneca a $1 billion grant to fund a 30,000 patient Phase III trial in the U.S. and the rights to 300 million doses of the AZD1222 vaccine that will start being delivered in October. Oxford began recruiting patients for a 10,260 patient, Phase II trial in May 2020

In a 28-day, 108 patient, Phase I, dose escalation, open-label trial, healthy Chinese patients developed antibodies after receiving a single immunization with CanSino’s Ad5-nCoV, but patients with high Ad5 antibody titers produced lower levels of COVID-19 antibodies. Most patients experienced a mild to moderate adverse event with the most common being injection site pain, fever, fatigue, headache and muscle pain. CanSino is developing the non-replicating adenovirus type-5 (Ad5) viral vector, (Ad5-nCoV) vaccine. Because the vaccine is Ad5 vectored and most adults have immunity to Ad5, the efficacy in older patients may not be as strong as in younger patients. Based on preliminary safety data from the first 14-days of the Phase I trial, CanoSino initiated a 500 patient, Phase II trial for Ad5-nCoV in May using the low and middle doses of the vaccine.

Novavax initiated a 130 patient, Phase I/II trial (NCT04368988) for NVX-CoV2373 in May 2020 with initial immunogenicity and safety results from the Phase 1 portion of the trial are expected in July 2020.

Moderna announced preliminary data from the NIAID Phase I, COVID-19 vaccine trial, where the lowest dose of mRNA-1273 (25 mcg) produced antibody levels similar to a recovered COVID-19 patient two weeks after the second dose of the vaccine. The 100mcg dose produced higher antibody levels than recovered patients. Patients that received the 250 mcg dose had a higher incidence of transient adverse events, so the Phase II trial will use 50 mcg and 100 mcg doses. The Phase II trial is forecast to begin in May 2020 and a Phase III trial in July 2020. Moderna hopes to file a BLA for mRNA-1273 in early 2021.

Commentary on recent COVID-19 news

The data currently available for COVID-19 treatments is very preliminary and does not demonstrate nor disprove efficacy. Most data available are from case reports, case series and small trials with methodological problems such as not controlling for confounders (i.e. additional antivirals used, mixed populations, poorly defined outcomes). ClinicalTrials.gov lists over 1,000 trials (1,087 in mid-May). As an example, there are 145 trials of hydroxychloroquine. The sample size in 32 trials is < 100, 12 trials are non-randomized, and 10 trials have no control group. This should be kept in mind as news reports from unreviewed, unedited articles are leaked. These studies may have design flaws, inaccurate or incomplete descriptions of results or missing information. Articles available in the editorial site MedRixiv have increased 400% from the end of 2019 (586 in the last 15-weeks of 2019) compared to early 2020 (2,572 in the first 15-weeks of 2020).

Most often the problem in the small studies involves several drugs that may have antiviral properties included in the supportive care of the patient. Therefore, it is unclear which treatment(s) produced an effect. Another problem is when the drug is not given until 1-2 weeks after the patient develops symptoms, which may be too late to have a full effect. So, review the most recent guidelines from the NIH, CDC or a major medical group, optimize supportive care according to their recommendations, and consider an investigative treatment as a shared decision with the patient and in the context of a clinical trial.

Two editorials discuss the problems with current research in more detail and included not only drugs and vaccines, but also preventive measures such as masks.

​A retrospective review of 1,438 patients in New York hospitalized for COVID-19 infection found no difference for in-hospital mortality with hydroxychloroquine, azithromycin, or both compared to not receiving either drug.

Anakinra

In a 21-day, 45 patient, non-randomized, observational trial, the addition of anakinra to hydroxychloroquine and lopinavir/ritonavir reduced serum C-reactive protein and improved respiratory function in 72% of patients compared to 50% in a historical cohort that had not received anakinra in patients with moderate-to-severe ARDS from COVID-19 that were managed with non-invasive ventilation outside of the ICU. Survival was 90% with anakinra and 50% without the drug at 21 days.

Tocilizumab

In a 21 patient, Chinese, uncontrolled retrospective study of patients with severe or critical COVID-19, tocilizumab was added after 7-days of standard treatment. At the time of the study, standard treatment was lopinavir/ritonavir, interferon, ribavirin and glucocorticoids. Fevers and elevated C-reactive protein levels normalized, and levels of IL-6 and other proinflammatory cytokines declined within 24 hours of tocilizumab administration. Within the first 5-days, there was a decrease in the use of supplemental oxygen in 15 patients.

Favipiravir

The Russian Direct Investment Fund announced interim results from a 330 patient Russian trial, where 24/40 (60%) of patients treated with favipiravir were negative for COVID-19 within five days compared to 30% in the standard therapy group. The press release did not specify how many patients were in the standard care group, how patients were tested for COVID-19, nor what other therapies are part of standard care for COVID-19 in Russia. The trial is expected to be completed by the end of May 2020.

In mid-April, there were 657 COVID-19 trials with 304 of the trials being listed as active or recruiting. It is hoped that by coordinating trials, research centers will not be overwhelmed, and patient recruitment will be improved. The steering committee will also prioritize research on the most promising candidates.

A description of ACTIV’s strategy to develop successful vaccines is provided by Anthony Fauci, MD, along with other government physicians and academic researchers. The report describes approaches to develop vaccines and scale them up to meet worldwide needs. The benefits and challenges of each type of vaccine is discussed along with the need to have multiple vaccines.

The journal Nature provided a graphical description of the different types of methods to create a vaccine that are currently being used to work on a vaccine for COVID-19.

The U.S. Department of Health and Human Services announced that six states have received a supply of remdesivir, and seven more states will receive a supply this week. HHS expects a supply to be delivered to each state from the 607,000 vials of remdesivir donated to the Federal Stockpile by Gilead. State health departments will decide on distribution within their state. HHS advised healthcare providers caring for patients with severe COVID-19 on ventilators or ECMO, who wish to use remdesivir, to contact their state health department to request a supply of the drug.

In a 127 patient, open-label, Phase II trial, treatment with lopinavir/ritonavir, ribavirin and interferon beta-1b reduced the time to a negative nasopharyngeal swab for COVID-19 compared to lopinavir/ritonavir and ribavirin from 12 days to seven days in hospitalized adults with COVID-19 in Hong Kong. Alleviation of symptoms (NEWS2 score of 0) was also reduced from eight days in the control group to four days in the interferon group.

BioNTech and Pfizer initiated a 200 patient, Phase I/II trial in Germany in April and a second 360 patient Phase I/II trial in the U.S. in May. Four vaccine candidates are being tested. Three require two doses, while the fourth contains self-amplifying mRNA and requires a single dose. Pfizer expects initial data from the trials in May or June with a successful vaccine candidate moving to larger trials and possibly emergency use or accelerated approval in the 4Q20.

Sanofi and GlaxoSmithKline have agreed to work together to develop a vaccine for COVID-19. The companies will use Sanofi’s S-protein COVID-19 antigen based on the company’s recombinant DNA tech in combination with GSK’s pandemic adjuvant technology. The recombinant DNA platform is the same one used to create the quadrivalent influenza vaccine FluBlok. GSK’s vaccine adjuvant reduces the amount of antigen required for a dose enabling a quicker way to scale up production. Both companies have the capacity to manufacture vaccines on a global scale and project the capacity to manufacture over a billion doses. The companies plan to initiate a large Phase I/II trial with several hundred patients in September 2020. A Phase III trial is planned for late 2020 or early 2021. The companies hope to file a BLA in the second half of 2021.

The FDA approved an emergency use authorization (EUA) for remdesivir to treat hospitalized patients with severe COVID-19. The U.S. Government will control distribution through AmerisourceBergen or government agencies based on hospital allocations set by the Federal Emergency Management Agency (FEMA). The allocation plan was approved by the White House Coronavirus Task Force. AmerisourceBergen will be told by FEMA which hospitals to send remdesivir to and how much of the drug to send. FEMA and HHS are developing a long-term strategy for allocation strategy of remdesivir. No list is posted regarding which hospitals will receive remdesivir or how much a hospital will receive. AmerisourceBergen contacts hospitals to let them know they will be receiving a drug supply. If you have not heard from AmerisourceBergen, you can ask about your hospital’s status by emailing the wholesaler at remdesivir@amerisourcebergen.com You will need to provide your facility name, ship to address with zip code, your Health Industry Number and your DEA number. Gilead is setting up agreements with pharmaceutical manufacturers to produce remdesivir for Europe, Asia and the developing world through 2022 in order to meet global needs.

COVID-19 Vaccines

BioNTech and Pfizer initiated a 200 patient, Phase I/II trial in Germany in April and a second 360 patient Phase I/II trial in the U.S. in May. Four vaccine candidates are being tested. Three require two doses, while the fourth contains self-amplifying mRNA and requires a single dose. Pfizer expects initial data from the trials in May or June with a successful vaccine candidate moving to larger trials and possibly emergency use or accelerated approval in the 4Q20.

Sanofi and GlaxoSmithKline have agreed to work together to develop a vaccine for COVID-19. The companies will use Sanofi’s S-protein COVID-19 antigen based on the company’s recombinant DNA tech in combination with GSK’s pandemic adjuvant technology. The recombinant DNA platform is the same one used to create the quadrivalent influenza vaccine FluBlok. GSK’s vaccine adjuvant reduces the amount of antigen required for a dose enabling a quicker way to scale up production. Both companies have the capacity to manufacturer vaccines on a global scale and project the capacity to manufacturer over a billion doses. The companies plan to initiate a large Phase I/II trial with several hundred patients in September 2020. A Phase III trial is planned for late 2020 or early 2021. The companies hope to a BLA in the second half of 2021.

The FDA approved an emergency use authorization (EUA) for remdesivir to treat hospitalized patients with severe COVID-19. The U.S. Government will control distribution through authorized wholesalers or government agencies. The government will tell the wholesalers where they can ship drug supplies. The initial emphasis will be on areas with the highest number of cases. Gilead has not announced pricing for remdesivir. The initial supply from the Federal Stockpile is from 1.5 million doses donated by Gilead to the U.S. and other countries.

ICER released a preliminary pricing review for remdesivir on 5/1/2020. ICER developed two pricing estimates. One is a cost recovery pricing estimate, based on a review of the cost of producing the final finished product. ICER estimated a cost recovery price of $1 per dose or $10 for a 10-day course and $5 for a 5-day course. Using a threshold price at $50,000 per incremental quality-adjusted life year (and equal value of a life-year gained) and the benefits seen in the Adaptive COVID-19 Treatment Trial (ACTT), ICER estimated a cost-effective price of $4,460 for a 10-day course of remdesivir assuming a mortality benefit and $390 with no mortality benefit.The EMA is reviewing clinical data for remdesivir with the possibility of accelerated approval.

Remestemcel-L

Mesoblast is evaluating remestemcel-L as a treatment for moderate-to-severe acute respiratory distress syndrome (ARDS) due to COVID-19 in a 300 patient, Phase I/II trial (NCT04366323).

COVID-19 Vaccine

The U.S. is establishing Operation Warp Speed to speed the development of a vaccine for COVID-19. Operation Warp Speed will coordinate the effort of pharmaceutical companies, government agencies and the military. Federal money will fund the program with a goal of having 300 million doses of vaccine available by January. The program will use government resources to quickly perform tests in animals, so human clinical trials can be launched as soon as possible. In order to achieve the goal of vaccine availability, vaccines may be manufactured before it is known if they will work. Many doses may be wasted before an effective vaccine is identified. Creating a vaccine in 12-18 months would be unprecedented. It took five years for approval of an Ebola vaccine.

Oxford University is evaluating a COVID-19 vaccine that uses a genetically modified non-replicating adenovirus that has been genetically modified to contain spike proteins from COVID-19, which should cause the body to produce antigens as the virus infects cells to prune the spike protein. AstraZeneca signed an agreement with Oxford University to take over development, manufacturing and distribution of the vaccine. AZ’s COVID-19 vaccine is currently in a Phase I trial being conducted by Oxford University with results expected in early summer. If successful, a 5,000 patient trial is planned to begin in the fall.

Moderna has entered an agreement with Swiss pharmaceutical company Lonzo to help manufacture Moderna’s mRNA-1273 COVID-19 vaccine. Lonzo will begin manufacturing the vaccine this summer at a U.S. facility and will expand manufacturing to other locations in order to scale up to 1 billion doses per year. If Moderna’s Phase I study is successful the company will initiate a 600 patient, Phase II trial, where patients will be given two doses, 28-days apart, of mRNA-1273 low dose (50 micrograms), high dose (250 micrograms) or placebo. Half of the patients enrolled in the trial will be older than 55.

The FDA approved an emergency use authorization (EUA) for remdesivir to treat hospitalized patients with severe COVID-19. The FDA defines severe COVID-19 as patients with low blood oxygen (SpO2 of 94% or less) that require supplemental oxygen with or without a mechanical ventilator or ECMO. The drug is approved to be administered in hospitalized patients. The U.S. Government will control distribution through authorized distributors or government agencies. A Fact Sheet is available for Heath Care Providers that reviews the treatment criteria, dosing, administration and monitoring of the patients receiving the drug. Remdesivir is given for 10 days in patients on ventilators or ECMO. Patients not receiving breathing support are administered the drug for 5 days, which can be extended to ten days if improvement is not seen. A Patient Fact Sheet is also available and must be made available to patients. Remdesivir does not have full FDA authorization and is only approved for use under the EUA for the patients described above.